title: Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys.
abstract: OBJECTIVE
  Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans.
  
  
  METHODS
  Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2-humanized antibody, hRS7. The immunoconjugates were characterized in vitro for stability, binding, and cytotoxicity. Efficacy was tested in five different human solid tumor-xenograft models that expressed Trop-2 antigen. Toxicity was assessed in mice and in Cynomolgus monkeys.
  
  
  RESULTS
  The hRS7 conjugates of the two SN-38 derivatives were equivalent in drug substitution (∼ 6), cell binding (K(d) ∼ 1.2 nmol/L), cytotoxicity (IC(50) ∼ 2.2 nmol/L), and serum stability in vitro (t/(½) ∼ 20 hours). Exposure of cells to the ADC demonstrated signaling pathways leading to PARP cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted. Significant antitumor effects were produced by hRS7-SN-38 at nontoxic doses in mice bearing Calu-3 (P ≤ 0.05), Capan-1 (P < 0.018), BxPC-3 (P < 0.005), and COLO 205 tumors (P < 0.033) when compared to nontargeting control ADCs. Mice tolerated a dose of 2 × 12 mg/kg (SN-38 equivalents) with only short-lived elevations in ALT and AST liver enzyme levels. Cynomolgus monkeys infused with 2 × 0.96 mg/kg exhibited only transient decreases in blood counts, although, importantly, the values did not fall below normal ranges.
  
  
  CONCLUSIONS
  The anti-Trop-2 hRS7-CL2A-SN-38 ADC provides significant and specific antitumor effects against a range of human solid tumor types. It is well tolerated in monkeys, with tissue Trop-2 expression similar to humans, at clinically relevant doses, and warrants clinical investigation.
authors.affiliation: Immunomedics, Inc, Morris Plains, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.forename: Serengulam V
authors.initials: SV
authors.lastname: Govindan
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: Preeti
authors.initials: P
authors.lastname: Trisal
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000737:chemistry / Q000627:therapeutic use*; D000077146:Irinotecan; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D008992:Monkey Diseases / Q000188:drug therapy / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; D007074:Immunoglobulin G; C499380:TACSTD2 protein, human; D000077146:Irinotecan; D002166:Camptothecin